Hippocampal neurogenesis and neuroinflammation after cranial irradiation with (56)Fe particles.

1Department of Neurological Surgery, University of California San Francisco, San Francisco, CA 94110, USA.

Abstract

Exposure to heavy-ion radiation is considered a potential health risk in long-term space travel. In the central nervous system (CNS), loss of critical cellular components may lead to performance decrements that could ultimately compromise mission goals and long-term quality of life. Hippocampal-dependent cognitive impairments occur after exposure to ionizing radiation, and while the pathogenesis of this effect is not yet clear, it may involve the production of newly born neurons (neurogenesis) in the hippocampal dentate gyrus. We irradiated mice with 0.5-4 Gy of (56)Fe ions and 2 months later quantified neurogenesis and numbers of activated microglia as a measure of neuroinflammation in the dentate gyrus. Results showed that there were few changes after 0.5 Gy, but that there was a dose-related decrease in hippocampal neurogenesis and a dose-related increase in numbers of newly born activated microglia from 0.5-4.0 Gy. While those findings were similar to what was reported after X irradiation, there were also some differences, particularly in the response of newly born glia. Overall, this study showed that hippocampal neurogenesis was sensitive to relatively low doses of (56)Fe particles, and that those effects were associated with neuroinflammation. Whether these changes will result in functional impairments or if/how they can be managed are topics for further investigation.

The effects of 56Fe-particle radiation on newly born cells in the dentate subgranular zone of mice. One month after irradiation mice received a single daily injection of 5-bromo-2′deoxyuridine (BrdU) for 7 consecutive days. Three weeks later, tissues were collected and immunohistochemistry and confocal microscopic analyses were done to quantify the numbers of cells co-labeled with BrdU and cell-specific antibodies. Cell numbers represented an estimate of the total number of positively labeled cells in the subgranular zone in both hemispheres. Values for irradiated mice were compared to those for nonirradiated controls. Panel A: Total numbers of BrdU-positive cells decreased slightly over the dose range of 0–2 Gy; the increase after 4 Gy largely represents newly born activated microglia (see Fig. 2). Panel B: Newly born neurons, which were labeled with an antibody against NeuN, showed significant decreases at all doses greater than 0.5 Gy. Panel C: Newly born astrocytes, labeled with an antibody against GFAP, showed substantial decreases after 0.5 and 1.0 Gy. The relative increases seen from 2–4 Gy likely represent a reactive gliosis but could also involve, in part, a regenerative response in GFAP-producing stem cells. Panel D: Newly born oligodendrocytes, which were labeled with an antibody against NG2, showed significant decreases after doses greater than 0.5 Gy. Each bar represents the mean for five or six mice; error bars are standard errors of the means. *P < 0.05 after adjustment for multiple comparisons.

The effects of 56Fe-particle radiation on newly born activated microglia in the dentate subgranular zone of mice. One month after irradiation, mice received a single daily injection of 5-bromo-2′deoxyuridine (BrdU) for 7 consecutive days. Three weeks later, tissues were collected and immunohistochemistry and confocal microscopic analyses were done to quantify the numbers of cells co-labeled with BrdU and CD68. Cell numbers represented an estimate of the total number of positively labeled cells in the dentate subgranular zone in both hemispheres. Compared to nonirradiated controls, there were significant dose-related increases in the numbers of double-labeled cells at all doses greater than 0.5 Gy. Each bar represents the mean for five or six mice; error bars are standard errors of the means. *P < 0.05 after adjustment for multiple comparisons.

The effects of 56Fe-particle radiation on total numbers of activated microglia in the dentate gyrus of mice. Cell numbers/unit area (mm2) were determined from four representative coronal sections of the dentate gyrus at the level of the dorsal hippocampus. While there tended to be more activated microglia in all the irradiated groups, none of the changes were significant. Each bar represents the mean for five or six mice, and error bars are standard errors of the means.